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Targeting the Ras-Ral Effector Pathway for Cancer Treatment

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Targeting the Ras-Ral Effector Pathway for Cancer Treatment TARGETING THE RAS-RAL EFFECTOR PATHWAY FOR CANCER TREATMENT Leanna R. Gentry A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmacology. Chapel Hill 2015 Approved by: Adrienne Cox Channing Der Lee Graves Klaus Hahn Gary Johnson ©2015 Leanna R. Gentry ALL RIGHTS RESERVED ii ABSTRACT LEANNA R. GENTRY: Targeting the Ras-Ral effector pathway for cancer treatment (Under the direction of Channing J. Der) The RAS oncogene is the most frequently mutated gene in human cancers, and this activated Ras oncoprotein has been shown to be required for both cancer initiation and maintenance. Great strides have been made in understanding Ras signaling in cancer since the discovery of its involvement in human cancers in 1982, with numerous Ras effector pathways and modes of Ras regulation having been identified as contributing to Ras-driven oncogenesis. However, there has been limited success in developing strategies for therapeutically targeting Ras-driven oncogenesis. One effort that has gained popularity in recent years is the inhibition of Ras effector signaling. The Ral (Ras-like) small GTPases, discovered shortly after Ras in an attempt to identify RAS-related genes, are activated downstream of Ras by Ral guanine nucleotide exchange factors (RalGEFs). The Ral family members have since emerged as critical regulators of key cellular processes and, importantly, have been characterized as playing a role in tumorigenesis and invasion of multiple cancer types. Interestingly, divergent roles for RalA and RalB are often observed in within a cancer. Due to the high affinity of Ral for GTP, which activates Ral upon binding, the Ral GTPase family cannot be targeted directly. Therefore, indirect inhibition of Ral must be considered for targeting Ral-dependent phenotypes in Ras-driven cancers. This could be achieved through inhibition of Ral association with the plasma membrane, which is thought to be required for its activation and subsequent signaling. Alternatively, downstream effectors of Ral with validated roles in cancer could be inhibited. Posttranslational processing of the CAAX motif located on the C-termini of Ral GTPases, among other proteins, has been considered essential for their proper subcellular localization, iii activation, and function. The first and essential step of this process is prenylation by GGTase. Prenylation signals for further CAAX processing by the enzymes RCE1 and ICMT, which are under consideration as therapeutic targets. We determined that the modifications regulated by these enzymes have distinct roles and consequences for Ral GTPases. We found that both RalA and RalB require RCE1 for association with the plasma membrane, and that the absence of RCE1 caused a sustained activation of both RalA and RalB. In contrast, ICMT deficiency disrupted plasma membrane localization of RalB but not RalA, whereas RalA depended on ICMT for efficient localization to recycling endosomes. Furthermore, ICMT deficiency caused increased stability of RalB protein but not RalA. Lastly, we found that palmitoylation was critical for proper subcellular localization of RalB but not RalA. In summary, we identified isoform-specific consequences of CAAX modifications that could be contributing to the divergent localization and activities of the Ral proteins. In order to address inhibiting Ral effectors, we sought to determine the effect of inhibiting TBK1, a kinase that is a validated effector of RalB, in pancreatic ductal adenocarcinoma, a disease characterized by greater than 90% of cases containing a K-Ras mutation. We found that a novel small molecule inhibitor of TBK1, while effective at inhibiting signaling, had a minimal effect on pancreatic cancer cell proliferation in vitro and in vivo. However, when combined with inhibition of ERK1/2, we found a synergistic proliferation defect and induction of apoptosis. This suggests combination approaches with TBK1 inhibitors may provide therapeutic benefit in the treatment of K- Ras-driven pancreatic cancer. Overall, this work provides further insight into strategies for targeting Ral for the treatment of cancer. iv ACKNOWLEDGEMENTS I want to thank my mentor, Dr. Channing Der, for teaching me to be independent and allowing me to take the science in my own direction while keeping me focused. I am fortunate to have been a part of the Der lab, and thank my fellow lab members who made this experience memorable and enjoyable. In particular, I want to thank Nicole Baker for being a wonderful and supportive friend from the first day of graduate school. I am thankful for Dr. Adrienne Cox, who was always there with her encouragement and advice when it came to both science and life. I would also like to thank my committee members, Drs. Gary Johnson, Lee Graves, and Klaus Hahn, for their creative ideas and insightful questions that have helped me complete this dissertation. I especially thank my parents, Gary and Mamta Gentry, for always encouraging me to pursue my love of learning and for teaching me to be tough. Without my mom’s unwavering support and my dad’s daily reminder to “have fun and be smart”, I would not have made it to this point, and I am eternally grateful to them. I am so fortunate to have them along with the best friends and family I could ever hope for. Thank you all for believing I could accomplish whatever I set my mind to, even on the days that I had trouble believing it for myself. Most importantly, I need to thank my husband, Garrett Keener. I am grateful for his unconditional love and support, and am so lucky to have had him by my side for this journey. Thank you for always knowing exactly how to make me smile. v TABLE OF CONTENTS LIST OF FIGURES ............................................................................................................... ix LIST OF ABBREVIATIONS ................................................................................................ x CHAPTER 1: INTRODUCTION ........................................................................................ 13 RAL GTPASE FAMILY ................................................................................................................................... 13 RAL PROTEIN STRUCTURE ......................................................................................................................... 14 RAL GEFS .......................................................................................................................................................... 17 RAL EFFECTORS ............................................................................................................................................. 21 RALBP1 ............................................................................................................................................................ 23 SEC5 AND EXO84 SUBUNITS OF THE EXOCYST ....................................................................................... 24 OTHER EFFECTORS ...................................................................................................................................... 25 POST-TRANSLATIONAL MODIFICATION AND REGULATION OF RAL FUNCTION .................... 26 RAL CAAX MODIFICATIONS ........................................................................................................................ 26 PHOSPHORYLATION REGULATION OF SUBCELLULAR LOCALIZATION AND EFFECTOR INTERACTION ................................................................................................................................................ 29 UBIQUITINATION .......................................................................................................................................... 30 DIVERGENT ROLES OF RAL IN CANCER ................................................................................................ 30 BLADDER CARCINOMA ................................................................................................................................ 31 COLORECTAL CARCINOMA ......................................................................................................................... 32 HEPATOCELLULAR CARCINOMA ............................................................................................................... 32 vi LUNG ADENOCARCINOMA .......................................................................................................................... 32 MALIGNANT PERIPHERAL NERVE SHEATH TUMORS. ............................................................................ 33 MELANOMA .................................................................................................................................................... 34 OVARIAN CARCINOMA ................................................................................................................................. 34 PANCREATIC DUCTAL ADENOCARCINOMA ............................................................................................. 35 PROSTATE CARCINOMA ............................................................................................................................... 36 SQUAMOUS CELL CARCINOMA .................................................................................................................. 36 CONCLUSIONS AND FUTURE PROSPECTS ............................................................................................. 36 CHAPTER
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